Article abstract
Nature Neuroscience 11, 28 - 35 (2008)
Published online: 9 December 2007 | doi:10.1038/nn2022
Netrin signal transduction and the guanine nucleotide exchange factor DOCK180 in attractive signaling
Xiaoling Li1,5, Xue Gao1,5, Guofa Liu1,5, Wencheng Xiong2, Jane Wu1,3 & Yi Rao1,4
Abstract
Netrins are prototypical axon guidance cues whose attractive signaling requires the small GTPase Rac1. It remains unclear how Rac1 is regulated in the netrin pathway. DOCK180 is a member of a new family of guanine nucleotide exchange factors for Rho GTPases. Here we provide evidence implicating DOCK180 in netrin signal transduction. Netrin promoted the formation of a protein-protein interaction complex that included DOCK180 and the netrin receptor deleted in colorectal carcinoma (DCC). Inhibition of DOCK180 reduced activation of Rac1 by netrin. Both axon outgrowth and axon attraction induced by netrin were inhibited after DOCK180 knockdown in vertebrate neurons. The in vivo functional role of DOCK180 was demonstrated by its requirement for projection of commissural axons in the neural tube. These findings indicate that netrin stimulation recruits DOCK180 through DCC, which then activates small GTPases, suggesting an essential role for DOCK180 in mediating attractive responses by neurons to netrin-1.
- Department of Neurology, Northwestern University Feinberg School of Medicine, 303 E. Superior Avenue, Chicago, Illinois 60611, USA.
- Program of Developmental Neurobiology, Institute of Molecular Medicine and Genetics, Department of Neurology, 1120 15th Street, CA 4010, Medical College of Georgia, Augusta, Georgia 30912, USA.
- Robert H. Lurie Comprehensive Cancer Center and the Center for Genetic Medicine, Northwestern University Feinberg School of Medicine, 303 E. Superior Avenue, Lurie 6–117, Chicago, Illinois 60611, USA.
- School of Life Sciences, Beijing University, Beijing 100871, China.
- These authors contributed equally to this work.
Correspondence to: Jane Wu1,3 e-mail: jane-wu@northwestern.edu
Correspondence to: Yi Rao1,4 e-mail: y-rao@northwestern.edu
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